iBiology

https://www.ibiology.org/cell-biology/protein-sorting Eukaryotic cells have many different membrane-bound organelles with distinct functions and characteristic shapes. How does this happen? Dr. Tom Rapoport explains the important role of protein sorting in determining organelle shape and function. In his first talk, Dr. Tom Rapoport explains that eukaryotic cells contain many membrane-bound organelles each of which has a characteristic shape and distinctive functions that are carried out by specific proteins. Most proteins are made in the cytosol but must move to different cellular destinations. Protein sorting is determined by signal sequences on the proteins that act as “zip codes”. Many proteins sort first to the endoplasmic reticulum (ER) before moving to other intracellular organelles or the plasma membrane. Rapoport explains that as a protein is translated, its signal sequence causes the nascent protein to insert into the Sec61 channel on the ER membrane. The polypeptide segment following the signal sequence will then be translocated across the membrane. Solving the structure of Sec61 channel allowed Rapoport’s lab to understand how proteins, which are typically hydrophilic, can be transported across a lipid membrane. It also helped them determine how Sec 61 differentiates between secreted proteins which need to be released into the ER lumen and transmembrane proteins which need to be anchored in the ER membrane. This improved knowledge of protein sorting helps us to better understand how organelles are formed and how they function. The ER is a vast network that includes different domains with different functions. The rough ER consists of sheets with associated ribosomes and is involved in protein translation. The smooth ER consists of tubules and is important for lipid synthesis and Ca2+ transport. In his second talk, Rapoport explains how his lab identified proteins needed to generate and maintain a tubular ER network. They found two families of proteins that are required to form the high membrane curvature of tubules, and membrane-bound GTPases that fuse the tubules together into a network. The tubule-shaping proteins are also important in forming the edges of the ER sheets. In mammalian cells, however, another set of proteins is required to act as spacers between the membrane sheets. Using ultra-thin section electron microscopy, Rapoport’s lab, in collaboration with others, was able to show that stacked ER sheets are held together by helicoidal membrane connections forming a “parking-garage” like structure. Speaker Biography: Dr. Tom Rapoport has been a Professor of Cell Biology at Harvard Medical School since 1995 and a Howard Hughes Medical Institute Investigator since 1997. Prior to joining Harvard, Rapoport was a Professor at the Institute for Molecular Biology in East Berlin, which later became the Max-Delbrück Institute for Molecular Medicine. Rapoport received his PhD from Humboldt University of Berlin. Rapoport’s research focuses on the understanding how organelles, in particular the endoplasmic reticulum (ER), derives its characteristic shape and performs its specific functions. He has had a long standing interest in how proteins are translocated across organelle membranes. His pioneering research has been recognized with many awards including the Max-Delbrück Medal in 2005, the Sir Hans Kreb Medal in 2007, and the Schleiden Medal in 2011, among many others. Rapoport is a member of the National Academy of Sciences, USA and the German Academy of Sciences, Leopoldina. He is also a Fellow of the American Association for the Advancement of Science (AAAS). Learn more about Rapoport’s research here: http://rapoport.hms.harvard.edu and here: https://www.hhmi.org/scientists/tom-rapoport

https://www.ibiology.org/cell-biology/protein-sorting Eukaryotic cells have many different membrane-bound organelles with distinct functions and characteristic shapes. How does this happen? Dr. Tom Rapoport explains the important role of protein sorting in determining organelle shape and function. In his first talk, Dr. Tom Rapoport explains that eukaryotic cells contain many membrane-bound organelles each of which has a characteristic shape and distinctive functions that are carried out by specific proteins. Most proteins are made in the cytosol but must move to different cellular destinations. Protein sorting is determined by signal sequences on the proteins that act as “zip codes”. Many proteins sort first to the endoplasmic reticulum (ER) before moving to other intracellular organelles or the plasma membrane. Rapoport explains that as a protein is translated, its signal sequence causes the nascent protein to insert into the Sec61 channel on the ER membrane. The polypeptide segment following the signal sequence will then be translocated across the membrane. Solving the structure of Sec61 channel allowed Rapoport’s lab to understand how proteins, which are typically hydrophilic, can be transported across a lipid membrane. It also helped them determine how Sec 61 differentiates between secreted proteins which need to be released into the ER lumen and transmembrane proteins which need to be anchored in the ER membrane. This improved knowledge of protein sorting helps us to better understand how organelles are formed and how they function. The ER is a vast network that includes different domains with different functions. The rough ER consists of sheets with associated ribosomes and is involved in protein translation. The smooth ER consists of tubules and is important for lipid synthesis and Ca2+ transport. In his second talk, Rapoport explains how his lab identified proteins needed to generate and maintain a tubular ER network. They found two families of proteins that are required to form the high membrane curvature of tubules, and membrane-bound GTPases that fuse the tubules together into a network. The tubule-shaping proteins are also important in forming the edges of the ER sheets. In mammalian cells, however, another set of proteins is required to act as spacers between the membrane sheets. Using ultra-thin section electron microscopy, Rapoport’s lab, in collaboration with others, was able to show that stacked ER sheets are held together by helicoidal membrane connections forming a “parking-garage” like structure. Speaker Biography: Dr. Tom Rapoport has been a Professor of Cell Biology at Harvard Medical School since 1995 and a Howard Hughes Medical Institute Investigator since 1997. Prior to joining Harvard, Rapoport was a Professor at the Institute for Molecular Biology in East Berlin, which later became the Max-Delbrück Institute for Molecular Medicine. Rapoport received his PhD from Humboldt University of Berlin. Rapoport’s research focuses on the understanding how organelles, in particular the endoplasmic reticulum (ER), derives its characteristic shape and performs its specific functions. He has had a long standing interest in how proteins are translocated across organelle membranes. His pioneering research has been recognized with many awards including the Max-Delbrück Medal in 2005, the Sir Hans Kreb Medal in 2007, and the Schleiden Medal in 2011, among many others. Rapoport is a member of the National Academy of Sciences, USA and the German Academy of Sciences, Leopoldina. He is also a Fellow of the American Association for the Advancement of Science (AAAS). Learn more about Rapoport’s research here: http://rapoport.hms.harvard.edu and here: https://www.hhmi.org/scientists/tom-rapoport

https://www.ibiology.org/cell-biology/protein-phosphatases Kinases and phosphatases perform a balancing act in cells by adding and removing phosphate groups from proteins. Dr. Bertolotti shows us that inhibiting specific protein phosphatases can reduce misfolded protein accumulation and reduce neurodegenerative disease. There are many processes and signals in cells that must be turned on and off, sometimes very quickly. How is this done? One important way is via post-translational modification of proteins such as phosphorylation or dephosphorylation. In her first talk, Dr. Anne Bertolotti introduces us to protein phosphatases, the enzymes that remove phosphate from proteins and work in opposition to protein kinases. She gives a brief history of the early experiments that showed that phosphatases are vital to regulating the stability, localization and interactions of many proteins. Bertolotti also describes more recent work demonstrating that protein phosphatases are split enzymes with a catalytic subunit and a subunit that determines substrate specificity. This selective subunit makes phosphatases exquisitely specific and attractive targets for drug development. Bertolotti’s lab has had a long time interest in understanding protein folding and the role of misfolded proteins in neurodegenerative disease. In her second talk, Bertolotti explains how her lab found that selectively inhibiting the dephosphorylation of eIF2⍺, a translation initiation factor, led to a reduction in protein synthesis. Decreasing protein synthesis allowed cells to “catch up” with the degradation of misfolded proteins that may accumulate as a result of cell stress. Her lab went on to show that a selective small molecule phosphatase inhibitor had therapeutic effects in a mouse model of Charcot-Marie-Tooth disease; a disease that results from the accumulation of misfolded protein in the ER. This exciting result suggested that targeted inhibition of protein phosphatases may have therapeutic potential for neurodegenerative diseases. In her third talk, Bertolotti describes a platform developed by her lab that has allowed them to rationally identify selective protein phosphatase inhibitors. Using this platform her lab identified a novel small molecule phosphatase inhibitor that blocks the accumulation of misfolded proteins in the cytosol or nucleus and showed the therapeutic effects of the molecule in a model of Huntington’s disease. Speaker Biography: Dr. Anne Bertolotti’s research focuses on understanding and preventing the deposition of misfolded proteins in cells, a hallmark of numerous neurological diseases. Bertolotti has been a group leader at the MRC Laboratory of Molecular Biology in Cambridge, UK since 2006. Prior to joining the LMB, she was an Associate Professor at Ecole Normale Superieure in Paris from 2001-2006. Bertolotti did her PhD training at the Institute of Genetics and Molecular and Cellular Biology (IGBMC) near Strasbourg, France and she was a post-doctoral fellow at the Skirball Institute of Biomolecular Medicine at NYU School of Medicine in New York. Bertolotti was elected an EMBO Young Investigator in 2005 and an EMBO member in 2013. In 2014, she was awarded the Hooke Medal of the British Society for Cell Biology for her contributions to our understanding of abnormal protein folding. Bertolotti was elected a Fellow of the UK Academy of Medical Sciences in 2017. Learn more about Bertolotti’s research here: https://www2.mrc-lmb.cam.ac.uk/group-leaders/a-to-g/anne-bertolotti

https://www.ibiology.org/cell-biology/protein-phosphatases Kinases and phosphatases perform a balancing act in cells by adding and removing phosphate groups from proteins. Dr. Bertolotti shows us that inhibiting specific protein phosphatases can reduce misfolded protein accumulation and reduce neurodegenerative disease. There are many processes and signals in cells that must be turned on and off, sometimes very quickly. How is this done? One important way is via post-translational modification of proteins such as phosphorylation or dephosphorylation. In her first talk, Dr. Anne Bertolotti introduces us to protein phosphatases, the enzymes that remove phosphate from proteins and work in opposition to protein kinases. She gives a brief history of the early experiments that showed that phosphatases are vital to regulating the stability, localization and interactions of many proteins. Bertolotti also describes more recent work demonstrating that protein phosphatases are split enzymes with a catalytic subunit and a subunit that determines substrate specificity. This selective subunit makes phosphatases exquisitely specific and attractive targets for drug development. Bertolotti’s lab has had a long time interest in understanding protein folding and the role of misfolded proteins in neurodegenerative disease. In her second talk, Bertolotti explains how her lab found that selectively inhibiting the dephosphorylation of eIF2⍺, a translation initiation factor, led to a reduction in protein synthesis. Decreasing protein synthesis allowed cells to “catch up” with the degradation of misfolded proteins that may accumulate as a result of cell stress. Her lab went on to show that a selective small molecule phosphatase inhibitor had therapeutic effects in a mouse model of Charcot-Marie-Tooth disease; a disease that results from the accumulation of misfolded protein in the ER. This exciting result suggested that targeted inhibition of protein phosphatases may have therapeutic potential for neurodegenerative diseases. In her third talk, Bertolotti describes a platform developed by her lab that has allowed them to rationally identify selective protein phosphatase inhibitors. Using this platform her lab identified a novel small molecule phosphatase inhibitor that blocks the accumulation of misfolded proteins in the cytosol or nucleus and showed the therapeutic effects of the molecule in a model of Huntington’s disease. Speaker Biography: Dr. Anne Bertolotti’s research focuses on understanding and preventing the deposition of misfolded proteins in cells, a hallmark of numerous neurological diseases. Bertolotti has been a group leader at the MRC Laboratory of Molecular Biology in Cambridge, UK since 2006. Prior to joining the LMB, she was an Associate Professor at Ecole Normale Superieure in Paris from 2001-2006. Bertolotti did her PhD training at the Institute of Genetics and Molecular and Cellular Biology (IGBMC) near Strasbourg, France and she was a post-doctoral fellow at the Skirball Institute of Biomolecular Medicine at NYU School of Medicine in New York. Bertolotti was elected an EMBO Young Investigator in 2005 and an EMBO member in 2013. In 2014, she was awarded the Hooke Medal of the British Society for Cell Biology for her contributions to our understanding of abnormal protein folding. Bertolotti was elected a Fellow of the UK Academy of Medical Sciences in 2017. Learn more about Bertolotti’s research here: https://www2.mrc-lmb.cam.ac.uk/group-leaders/a-to-g/anne-bertolotti

https://www.ibiology.org/cell-biology/protein-phosphatases Kinases and phosphatases perform a balancing act in cells by adding and removing phosphate groups from proteins. Dr. Bertolotti shows us that inhibiting specific protein phosphatases can reduce misfolded protein accumulation and reduce neurodegenerative disease. There are many processes and signals in cells that must be turned on and off, sometimes very quickly. How is this done? One important way is via post-translational modification of proteins such as phosphorylation or dephosphorylation. In her first talk, Dr. Anne Bertolotti introduces us to protein phosphatases, the enzymes that remove phosphate from proteins and work in opposition to protein kinases. She gives a brief history of the early experiments that showed that phosphatases are vital to regulating the stability, localization and interactions of many proteins. Bertolotti also describes more recent work demonstrating that protein phosphatases are split enzymes with a catalytic subunit and a subunit that determines substrate specificity. This selective subunit makes phosphatases exquisitely specific and attractive targets for drug development. Bertolotti’s lab has had a long time interest in understanding protein folding and the role of misfolded proteins in neurodegenerative disease. In her second talk, Bertolotti explains how her lab found that selectively inhibiting the dephosphorylation of eIF2⍺, a translation initiation factor, led to a reduction in protein synthesis. Decreasing protein synthesis allowed cells to “catch up” with the degradation of misfolded proteins that may accumulate as a result of cell stress. Her lab went on to show that a selective small molecule phosphatase inhibitor had therapeutic effects in a mouse model of Charcot-Marie-Tooth disease; a disease that results from the accumulation of misfolded protein in the ER. This exciting result suggested that targeted inhibition of protein phosphatases may have therapeutic potential for neurodegenerative diseases. In her third talk, Bertolotti describes a platform developed by her lab that has allowed them to rationally identify selective protein phosphatase inhibitors. Using this platform her lab identified a novel small molecule phosphatase inhibitor that blocks the accumulation of misfolded proteins in the cytosol or nucleus and showed the therapeutic effects of the molecule in a model of Huntington’s disease. Speaker Biography: Dr. Anne Bertolotti’s research focuses on understanding and preventing the deposition of misfolded proteins in cells, a hallmark of numerous neurological diseases. Bertolotti has been a group leader at the MRC Laboratory of Molecular Biology in Cambridge, UK since 2006. Prior to joining the LMB, she was an Associate Professor at Ecole Normale Superieure in Paris from 2001-2006. Bertolotti did her PhD training at the Institute of Genetics and Molecular and Cellular Biology (IGBMC) near Strasbourg, France and she was a post-doctoral fellow at the Skirball Institute of Biomolecular Medicine at NYU School of Medicine in New York. Bertolotti was elected an EMBO Young Investigator in 2005 and an EMBO member in 2013. In 2014, she was awarded the Hooke Medal of the British Society for Cell Biology for her contributions to our understanding of abnormal protein folding. Bertolotti was elected a Fellow of the UK Academy of Medical Sciences in 2017. Learn more about Bertolotti’s research here: https://www2.mrc-lmb.cam.ac.uk/group-leaders/a-to-g/anne-bertolotti

https://www.ibiology.org/cell-biology/membrane-contact-sites The endoplasmic reticulum (ER) is a dynamic network of tubules that reaches throughout a cell. It interacts with other organelles at membrane contact sites. As Dr. Gia Voeltz explains, these sites are critical for Ca2+ regulation, lipid transport and defining sites of division for endosomes and other organelles. Many of us are used to seeing cartoons of cells with organelles shown as static, isolated structures. The endoplasmic reticulum is often shown looking like a stack of pancakes pushed up against the nuclear envelope. In her first talk, Dr. Gia Voeltz explains that recent advances in light microscopy have given us a very different view of organelles and their interactions. The ER is, in fact, an expansive, and highly dynamic, network of tubules that spreads throughout the cell. It interacts with other organelles such as the plasma membrane, endosomes, and mitochondria at points called membrane contact sites. Using beautiful fluorescent images and movies, Voeltz shows us that these ER membrane contact sites are important for many functions such as trafficking lipids and Ca2+ and determining where mitochondria divide and endosomes undergo fission. These exciting findings define a new cellular function for the ER. In her second lecture, Voeltz explains how her lab used a BioID strategy to identify some of the proteins found at membrane contact sites between the ER and endosomes; a difficult task given the transient nature of contact sites. They were able to identify a number of proteins responsible for marking the timing and location of endosome fission and for recruiting the ER to the bud. Depleting these proteins blocked cargo sorting to the Golgi. Voeltz’ lab is now working to determine how much of this machinery is conserved in processes such as the mitochondrial division. Speaker Biography: Dr. Gia Voeltz discovered her love for research as an undergraduate student at the University of California Santa Cruz. After graduation, she moved east to Yale University where she was a graduate student with Joan Steitz and studied RNA processing in Xenopus extracts. As a post-doctoral fellow in Tom Rapoport’s lab at Harvard, Voeltz tackled the question of how organelles, and in particular the endoplasmic reticulum, are shaped. Voeltz started her own lab at the University of Colorado, Boulder in 2006. She became an HHMI Faculty Scholar in 2016 and an HHMI Investigator in 2018. Her lab investigates how the ER interacts with other organelles such as the mitochondria and endosomes via membrane contact sites and how these contact sites may regulate organelle division and function. Learn more about Voeltz’ research here: https://www.voeltzlab.org

https://www.ibiology.org/cell-biology/membrane-contact-sites The endoplasmic reticulum (ER) is a dynamic network of tubules that reaches throughout a cell. It interacts with other organelles at membrane contact sites. As Dr. Gia Voeltz explains, these sites are critical for Ca2+ regulation, lipid transport and defining sites of division for endosomes and other organelles. Many of us are used to seeing cartoons of cells with organelles shown as static, isolated structures. The endoplasmic reticulum is often shown looking like a stack of pancakes pushed up against the nuclear envelope. In her first talk, Dr. Gia Voeltz explains that recent advances in light microscopy have given us a very different view of organelles and their interactions. The ER is, in fact, an expansive, and highly dynamic, network of tubules that spreads throughout the cell. It interacts with other organelles such as the plasma membrane, endosomes, and mitochondria at points called membrane contact sites. Using beautiful fluorescent images and movies, Voeltz shows us that these ER membrane contact sites are important for many functions such as trafficking lipids and Ca2+ and determining where mitochondria divide and endosomes undergo fission. These exciting findings define a new cellular function for the ER. In her second lecture, Voeltz explains how her lab used a BioID strategy to identify some of the proteins found at membrane contact sites between the ER and endosomes; a difficult task given the transient nature of contact sites. They were able to identify a number of proteins responsible for marking the timing and location of endosome fission and for recruiting the ER to the bud. Depleting these proteins blocked cargo sorting to the Golgi. Voeltz’ lab is now working to determine how much of this machinery is conserved in processes such as the mitochondrial division. Speaker Biography: Dr. Gia Voeltz discovered her love for research as an undergraduate student at the University of California Santa Cruz. After graduation, she moved east to Yale University where she was a graduate student with Joan Steitz and studied RNA processing in Xenopus extracts. As a post-doctoral fellow in Tom Rapoport’s lab at Harvard, Voeltz tackled the question of how organelles, and in particular the endoplasmic reticulum, are shaped. Voeltz started her own lab at the University of Colorado, Boulder in 2006. She became an HHMI Faculty Scholar in 2016 and an HHMI Investigator in 2018. Her lab investigates how the ER interacts with other organelles such as the mitochondria and endosomes via membrane contact sites and how these contact sites may regulate organelle division and function. Learn more about Voeltz’ research here: https://www.voeltzlab.org

https://www.ibiology.org/development-and-stem-cells/x-chromosome-inactivation The X chromosome is many time larger than the Y chromosome. To compensate for this genetic inequality, female mammalian cells undergo X chromosome inactivation of one X chromosome. Dr. Jeannie Lee explains the how and why of X chromosome inactivation. Part 3 of 3: And in her last talk, Lee describes how X inactivation is nucleated and spreads across the X chromosome. The Xist lncRNA is known to be necessary and sufficient for X inactivation. Lee describes experiments that identified the factors that tether Xist to the X chromosome and showed how Xist spreads to cover the entire X chromosome. She then goes on to explain that Xist blocks transcription in three ways: 1) Xist recruits factors that repress transcription via epigenetic modification such as histone methylation 2) Xist repels factors that open chromatin preparing it for transcription and 3) Xist changes the 3 dimensional organization of chromosomes. Lee ends with a model of our current understanding of the complex but critical process of X chromosome inactivation. Speaker Biography: Dr. Jeannie Lee is a Professor in the Department of Genetics at Harvard Medical School and in the Department of Molecular Biology at Massachusetts General Hospital (MGH). Her lab uses X chromosome inactivation as a model to study epigenetic regulation by long noncoding RNAs. Lee received her AB in biochemistry and molecular biology from Harvard University and her MD/PhD from the University of Pennsylvania School of Medicine. She was a postdoctoral fellow at the Whitehead Institute and a resident at MGH before joining Harvard/MGH as a faculty member in 1997. Lee was also an HHMI Investigator from 2001-2018. She is a member of the National Academy of Sciences and a Fellow of the American Association for the Advancement of Science. Lee has been honored with numerous awards including the 2016 Centennial Prize from the Genetics Society of America, the 2016 Lurie Prize from the Foundation for the National Institutes of Health, and the 2010 Molecular Biology Award from the National Academy of Sciences. In 2018, she was President of the Genetics Society of America. Learn more about Dr. Lee’s research here: https://www.x-inactivation-lee-lab.org

https://www.ibiology.org/development-and-stem-cells/x-chromosome-inactivation The X chromosome is many time larger than the Y chromosome. To compensate for this genetic inequality, female mammalian cells undergo X chromosome inactivation of one X chromosome. Dr. Jeannie Lee explains the how and why of X chromosome inactivation. Part 2 of 3: In her second talk, Lee elaborates on the early steps of X inactivation. Very early in development, cells “count” the number of X chromosomes and decide if one needs to be inactivated, and if so which one. There is a region of the X chromosome called the X inactivation center which is enriched in long non-coding RNAs (lncRNAs). Lee explains how she and others showed that by sensing the ratio of two specific lncRNAs the cell can determine how many X chromosomes are present. Further studies showed that two different lncRNAs are responsible for randomly determining which X chromosome will be inactivated. Finally, she discusses the hypothesis that the allelic choice mechanism depends on a transient chromosomal pairing event that occurs at the beginning of the dosage compensation process. Speaker Biography: Dr. Jeannie Lee is a Professor in the Department of Genetics at Harvard Medical School and in the Department of Molecular Biology at Massachusetts General Hospital (MGH). Her lab uses X chromosome inactivation as a model to study epigenetic regulation by long noncoding RNAs. Lee received her AB in biochemistry and molecular biology from Harvard University and her MD/PhD from the University of Pennsylvania School of Medicine. She was a postdoctoral fellow at the Whitehead Institute and a resident at MGH before joining Harvard/MGH as a faculty member in 1997. Lee was also an HHMI Investigator from 2001-2018. She is a member of the National Academy of Sciences and a Fellow of the American Association for the Advancement of Science. Lee has been honored with numerous awards including the 2016 Centennial Prize from the Genetics Society of America, the 2016 Lurie Prize from the Foundation for the National Institutes of Health, and the 2010 Molecular Biology Award from the National Academy of Sciences. In 2018, she was President of the Genetics Society of America. Learn more about Dr. Lee’s research here: https://www.x-inactivation-lee-lab.org

https://www.ibiology.org/development-and-stem-cells/x-chromosome-inactivation The X chromosome is many time larger than the Y chromosome. To compensate for this genetic inequality, female mammalian cells undergo X chromosome inactivation of one X chromosome. Dr. Jeannie Lee explains the how and why of X chromosome inactivation. Part 1 of 3: In mammals, sex is determined by a pair of unequal sex chromosomes. Genetically male mammals have an X and a Y chromosome while genetically female mammals have two X chromosomes. The X chromosome is many times larger than the Y chromosome. To compensate for this genetic inequality, female mammals undergo X chromosome inactivation in which one of the X chromosomes is randomly chosen to be silenced. X chromosome inactivation has been studied for over 50 years both because it is a physiologically important event and because it is an excellent model for studying epigenetic silencing of genes by long non-coding RNAs. In her first talk, Dr. Jeannie Lee gives an overview of the steps a cell must go through during X inactivation. These include “counting” the X chromosomes, deciding which X chromosome to inactivate, initiating the inactivation and spreading it across the chromosome, and finally maintaining inactivation of the same X chromosome for the rest of the life of the organism. Speaker Biography: Dr. Jeannie Lee is a Professor in the Department of Genetics at Harvard Medical School and in the Department of Molecular Biology at Massachusetts General Hospital (MGH). Her lab uses X chromosome inactivation as a model to study epigenetic regulation by long noncoding RNAs. Lee received her AB in biochemistry and molecular biology from Harvard University and her MD/PhD from the University of Pennsylvania School of Medicine. She was a postdoctoral fellow at the Whitehead Institute and a resident at MGH before joining Harvard/MGH as a faculty member in 1997. Lee was also an HHMI Investigator from 2001-2018. She is a member of the National Academy of Sciences and a Fellow of the American Association for the Advancement of Science. Lee has been honored with numerous awards including the 2016 Centennial Prize from the Genetics Society of America, the 2016 Lurie Prize from the Foundation for the National Institutes of Health, and the 2010 Molecular Biology Award from the National Academy of Sciences. In 2018, she was President of the Genetics Society of America. Learn more about Dr. Lee’s research here: https://www.x-inactivation-lee-lab.org

https://www.ibiology.org/immunology/cells-immune-system Brittany Anderton provides an overview of the major cells of the human immune system. The immune system is responsible for fighting infection and disease. It is comprised of many specialized cell types, all which work together to keep people healthy. In this short video, Dr. Brittany Anderton introduces the cells of the immune system. She compares and contrasts innate and adaptive immunity, and lays out the molecular interactions required to activate each type of response. Speaker Biography: Dr. Brittany Anderton obtained her PhD in biomedicine from UCSF in 2015. After that, she did a non-traditional postdoc at UC Davis where she studied the teaching and communication of biotechnology. Brittany has served as adjunct faculty at UC Davis and CSU Sacramento, where she taught introductory biology courses. At iBiology, she seeks to improve the teaching and communication of science using evidence from the learning and social sciences.

https://www.ibiology.org/genetics-and-gene-regulation/homologous-recombination Broken chromosomes naturally arise during DNA replication. In healthy cells, the breaks are repaired by homologous recombination. If the repair machinery is broken, cancer can result. Talk Overview: Dr. Haber begins his talk by explaining that broken chromosomes frequently arise during the process of DNA replication. In healthy cells, these double strand breaks (DSBs) are repaired by homologous recombination, an orderly process that preserves the genome. If the homologous recombination machinery is impaired, DNA truncations, translocations, and deletions often occur, resulting in genome instability and cancer. All mechanisms of homologous recombination have one common principal; the broken ends of the DNA are repaired by base pairing with a sequence that is identical or nearly identical and acts as a template for repair enzymes. Haber explains the general principles of homologous recombination and its critical role in maintaining genome stability. In his second talk, Haber explains in greater detail the molecular steps that take place during the repair of a DNA double strand break. It turns out that the process of mating type switching in S. cerevisiae requires the site- specific cutting and repair of a yeast chromosome and this is an excellent model for studying DNA DSB repair. Working in this system and using techniques such as Southern blots, PCR and chromatin immunoprecipitation, Haber’s group was able to identify the proteins and enzymatic steps in DNA repair. DNA synthesis that occurs during repair is much less accurate than normal DNA replication. Using the yeast mating type switching system, Haber’s lab identified base pair substitutions, frame shifts and other mutations that occur when the newly synthesized strand dissociates from the template strand during homologous recombination. Interestingly, Haber found that sometimes the newly synthesized strand will “jump” to a related but divergent template, even on another chromosome, and then jump back to complete the repair. Further experiments showed that this happens because the repair polymerase falls off the template with a very high frequency. Understanding why this occurs may help us to decipher the complex chromosomal rearrangements associated with certain human diseases. Speaker Biography: Jim Haber is Professor of Biology and Director of the Rosenstiel Basic Medical Sciences Research Center at Brandeis University. He received his A.B. degree in Biochemical Sciences at Harvard College and his Ph.D. in Biochemistry at U.C. Berkeley. After postdoctoral training at the University of Wisconsin in Madison, he joined the faculty at Brandeis University. He is a Fellow of the American Association for the Advancement of Science, the American Academy of Microbiology and the American Academy of Arts and Sciences, and a Member of the National Academy of Sciences. Haber’s lab has pioneered the real-time monitoring of the repair of double-strand chromosome breaks in yeast cells by using Southern blots, PCR and chromatin immunoprecipitation and has characterized many of the molecular steps in different mechanisms of double strand break repair by homologous recombination and non-homologous end-joining. His lab also investigates the DNA damage response by which cells arrest mitosis when cells suffer a single chromosome break. Learn more about Haber’s research here: http://www.bio.brandeis.edu/haberlab

https://www.ibiology.org/genetics-and-gene-regulation/homologous-recombination Broken chromosomes naturally arise during DNA replication. In healthy cells, the breaks are repaired by homologous recombination. If the repair machinery is broken, cancer can result. Talk Overview: Dr. Haber begins his talk by explaining that broken chromosomes frequently arise during the process of DNA replication. In healthy cells, these double strand breaks (DSBs) are repaired by homologous recombination, an orderly process that preserves the genome. If the homologous recombination machinery is impaired, DNA truncations, translocations, and deletions often occur, resulting in genome instability and cancer. All mechanisms of homologous recombination have one common principal; the broken ends of the DNA are repaired by base pairing with a sequence that is identical or nearly identical and acts as a template for repair enzymes. Haber explains the general principles of homologous recombination and its critical role in maintaining genome stability. In his second talk, Haber explains in greater detail the molecular steps that take place during the repair of a DNA double strand break. It turns out that the process of mating type switching in S. cerevisiae requires the site- specific cutting and repair of a yeast chromosome and this is an excellent model for studying DNA DSB repair. Working in this system and using techniques such as Southern blots, PCR and chromatin immunoprecipitation, Haber’s group was able to identify the proteins and enzymatic steps in DNA repair. DNA synthesis that occurs during repair is much less accurate than normal DNA replication. Using the yeast mating type switching system, Haber’s lab identified base pair substitutions, frame shifts and other mutations that occur when the newly synthesized strand dissociates from the template strand during homologous recombination. Interestingly, Haber found that sometimes the newly synthesized strand will “jump” to a related but divergent template, even on another chromosome, and then jump back to complete the repair. Further experiments showed that this happens because the repair polymerase falls off the template with a very high frequency. Understanding why this occurs may help us to decipher the complex chromosomal rearrangements associated with certain human diseases. Speaker Biography: Jim Haber is Professor of Biology and Director of the Rosenstiel Basic Medical Sciences Research Center at Brandeis University. He received his A.B. degree in Biochemical Sciences at Harvard College and his Ph.D. in Biochemistry at U.C. Berkeley. After postdoctoral training at the University of Wisconsin in Madison, he joined the faculty at Brandeis University. He is a Fellow of the American Association for the Advancement of Science, the American Academy of Microbiology and the American Academy of Arts and Sciences, and a Member of the National Academy of Sciences. Haber’s lab has pioneered the real-time monitoring of the repair of double-strand chromosome breaks in yeast cells by using Southern blots, PCR and chromatin immunoprecipitation and has characterized many of the molecular steps in different mechanisms of double strand break repair by homologous recombination and non-homologous end-joining. His lab also investigates the DNA damage response by which cells arrest mitosis when cells suffer a single chromosome break. Learn more about Haber’s research here: http://www.bio.brandeis.edu/haberlab

https://www.ibiology.org/genetics-and-gene-regulation/homologous-recombination Broken chromosomes naturally arise during DNA replication. In healthy cells, the breaks are repaired by homologous recombination. If the repair machinery is broken, cancer can result. Talk Overview: Dr. Haber begins his talk by explaining that broken chromosomes frequently arise during the process of DNA replication. In healthy cells, these double strand breaks (DSBs) are repaired by homologous recombination, an orderly process that preserves the genome. If the homologous recombination machinery is impaired, DNA truncations, translocations, and deletions often occur, resulting in genome instability and cancer. All mechanisms of homologous recombination have one common principal; the broken ends of the DNA are repaired by base pairing with a sequence that is identical or nearly identical and acts as a template for repair enzymes. Haber explains the general principles of homologous recombination and its critical role in maintaining genome stability. In his second talk, Haber explains in greater detail the molecular steps that take place during the repair of a DNA double strand break. It turns out that the process of mating type switching in S. cerevisiae requires the site- specific cutting and repair of a yeast chromosome and this is an excellent model for studying DNA DSB repair. Working in this system and using techniques such as Southern blots, PCR and chromatin immunoprecipitation, Haber’s group was able to identify the proteins and enzymatic steps in DNA repair. DNA synthesis that occurs during repair is much less accurate than normal DNA replication. Using the yeast mating type switching system, Haber’s lab identified base pair substitutions, frame shifts and other mutations that occur when the newly synthesized strand dissociates from the template strand during homologous recombination. Interestingly, Haber found that sometimes the newly synthesized strand will “jump” to a related but divergent template, even on another chromosome, and then jump back to complete the repair. Further experiments showed that this happens because the repair polymerase falls off the template with a very high frequency. Understanding why this occurs may help us to decipher the complex chromosomal rearrangements associated with certain human diseases. Speaker Biography: Jim Haber is Professor of Biology and Director of the Rosenstiel Basic Medical Sciences Research Center at Brandeis University. He received his A.B. degree in Biochemical Sciences at Harvard College and his Ph.D. in Biochemistry at U.C. Berkeley. After postdoctoral training at the University of Wisconsin in Madison, he joined the faculty at Brandeis University. He is a Fellow of the American Association for the Advancement of Science, the American Academy of Microbiology and the American Academy of Arts and Sciences, and a Member of the National Academy of Sciences. Haber’s lab has pioneered the real-time monitoring of the repair of double-strand chromosome breaks in yeast cells by using Southern blots, PCR and chromatin immunoprecipitation and has characterized many of the molecular steps in different mechanisms of double strand break repair by homologous recombination and non-homologous end-joining. His lab also investigates the DNA damage response by which cells arrest mitosis when cells suffer a single chromosome break. Learn more about Haber’s research here: http://www.bio.brandeis.edu/haberlab

https://www.ibiology.org/development-and-stem-cells/placental-development Dr. Mana Parast provides an introduction to placental development, the organ that every mammalian embryo needs for proper growth and development. The placenta derives from trophoblasts, embryonic cells located in the outermost layer of the embryo. Pre-eclampsia and other maternal factors can hinder placental development and therefore affect the development of the fetus. A better understanding on how defects associated with pregnancy disorders affect placental development could lead to novel therapeutics in the future. In her second seminar, Parast explains the different models to study human placental development in-vitro. Scientists can derive induced pluripotent stem cells (iPSCs) from umbilical cord cells. Parast’s laboratory first differentiates the iPSCs into trophoblasts cells which can then generate the different cells found in the placenta. Her laboratory uses these placental cells to study developmental complications by comparing cells derived from normal pregnancies to cells derived from non-normal pregnancies (e.g. patients born from mothers with pre-eclampsia). Speaker Biography: Dr. Mana Parast is a Professor in Residence at the University of California, San Diego. She earned her bachelor’s degree from the University of Rochester in 1994, and her medical (2002) and doctorate degree (2001) from the University of Virginia. She completed a residency in Anatomical Pathology at Emory University in 2005, and a fellowship in Women's and Perinatal Pathology at Brigham and Women's Hospital in 2006. Parast joined the faculty at University of California, San Diego in 2008, where she is the Director of Perinatal Pathology; in her research lab, she studies the differences in trophoblast differentiation that lead to abnormal placental development. Learn more about Parast research here: https://profiles.ucsd.edu/mana.parast

https://www.ibiology.org/development-and-stem-cells/placental-development Dr. Mana Parast provides an introduction to placental development, the organ that every mammalian embryo needs for proper growth and development. The placenta derives from trophoblasts, embryonic cells located in the outermost layer of the embryo. Pre-eclampsia and other maternal factors can hinder placental development and therefore affect the development of the fetus. A better understanding on how defects associated with pregnancy disorders affect placental development could lead to novel therapeutics in the future. In her second seminar, Parast explains the different models to study human placental development in-vitro. Scientists can derive induced pluripotent stem cells (iPSCs) from umbilical cord cells. Parast’s laboratory first differentiates the iPSCs into trophoblasts cells which can then generate the different cells found in the placenta. Her laboratory uses these placental cells to study developmental complications by comparing cells derived from normal pregnancies to cells derived from non-normal pregnancies (e.g. patients born from mothers with pre-eclampsia). Speaker Biography: Dr. Mana Parast is a Professor in Residence at the University of California, San Diego. She earned her bachelor’s degree from the University of Rochester in 1994, and her medical (2002) and doctorate degree (2001) from the University of Virginia. She completed a residency in Anatomical Pathology at Emory University in 2005, and a fellowship in Women's and Perinatal Pathology at Brigham and Women's Hospital in 2006. Parast joined the faculty at University of California, San Diego in 2008, where she is the Director of Perinatal Pathology; in her research lab, she studies the differences in trophoblast differentiation that lead to abnormal placental development. Learn more about Parast research here: https://profiles.ucsd.edu/mana.parast

https://www.ibiology.org/neuroscience/decision-making Anne Churchland shares her research on what happens in the brain when it makes decisions. How do brains make decisions? In this seminar, Dr. Anne Churchland tells us why understanding decision-making is important, and outlines common approaches to study decision-making in the lab using a variety of mammals. She describes findings that suggest accurate decision-making results from a combination of visual and auditory stimuli in both humans and rats, and tells of the discovery of an explore-exploit tradeoff that allows rats to respond optimally to changing environments. Dr. Churchland then outlines the major methods for tracking neural activity in the brain and shows how they have been used to determine that many brain areas are active during decision-making. She ends her talk with an overview of new directions in the field. In her second talk, Churchland outlines her group’s studies of the relationship between decision-making and action. She notes that in addition to methods to track neural activity, high-resolution videos of the decision-making process in mice provide valuable movement data. Using labeled calcium to visualize neural activity across the dorsal cortex, Churchland’s group measures that maps of the visual world are represented up to six times in each mouse brain! The Churchland group also found that neural activity appeared to be the same across novice and expert decision-makers. They developed a mathematical model to predict the influence of numerous variables on neural activity and found that movement-related variables accounted for a greater proportion of the variance in neural activity than decision-related variables. Specifically, spontaneous (non-instructed) movements had the greatest predicted influence on neural activity. They then validated their results at the single-neuron level using two-photon microscopy. Dr. Churchland ends her talk by highlighting a significant remaining question: what are the neural differences between novice and expert decision-makers? Speaker Biography: Anne Churchland is an Associate Professor at Cold Spring Harbor Laboratory. Her research group studies the neural circuits that underlie decision-making in mice and rats. Churchland received a B.A. from Wellesley College and a PhD in Neuroscience from the University of California, San Francisco. She began her research on decision making while she was a post-doctoral fellow with Dr. Michael Shadlen at the University of Washington. Churchland has received the McKnight Scholar Award, PEW Scholar in the Biomedical Sciences from the Pew Charitable Trusts, and the Klingenstein-Simons Fellowship in the Neurosciences from the Simons Foundation and the Esther A. and Joseph Klingenstein Fund. Learn more about Dr. Churchland’s research here: https://www.cshl.edu/research/faculty-staff/anne-churchland/#research-profile

https://www.ibiology.org/neuroscience/decision-making Anne Churchland shares her research on what happens in the brain when it makes decisions. How do brains make decisions? In this seminar, Dr. Anne Churchland tells us why understanding decision-making is important, and outlines common approaches to study decision-making in the lab using a variety of mammals. She describes findings that suggest accurate decision-making results from a combination of visual and auditory stimuli in both humans and rats, and tells of the discovery of an explore-exploit tradeoff that allows rats to respond optimally to changing environments. Dr. Churchland then outlines the major methods for tracking neural activity in the brain and shows how they have been used to determine that many brain areas are active during decision-making. She ends her talk with an overview of new directions in the field. In her second talk, Churchland outlines her group’s studies of the relationship between decision-making and action. She notes that in addition to methods to track neural activity, high-resolution videos of the decision-making process in mice provide valuable movement data. Using labeled calcium to visualize neural activity across the dorsal cortex, Churchland’s group measures that maps of the visual world are represented up to six times in each mouse brain! The Churchland group also found that neural activity appeared to be the same across novice and expert decision-makers. They developed a mathematical model to predict the influence of numerous variables on neural activity and found that movement-related variables accounted for a greater proportion of the variance in neural activity than decision-related variables. Specifically, spontaneous (non-instructed) movements had the greatest predicted influence on neural activity. They then validated their results at the single-neuron level using two-photon microscopy. Dr. Churchland ends her talk by highlighting a significant remaining question: what are the neural differences between novice and expert decision-makers? Speaker Biography: Anne Churchland is an Associate Professor at Cold Spring Harbor Laboratory. Her research group studies the neural circuits that underlie decision-making in mice and rats. Churchland received a B.A. from Wellesley College and a PhD in Neuroscience from the University of California, San Francisco. She began her research on decision making while she was a post-doctoral fellow with Dr. Michael Shadlen at the University of Washington. Churchland has received the McKnight Scholar Award, PEW Scholar in the Biomedical Sciences from the Pew Charitable Trusts, and the Klingenstein-Simons Fellowship in the Neurosciences from the Simons Foundation and the Esther A. and Joseph Klingenstein Fund. Learn more about Dr. Churchland’s research here: https://www.cshl.edu/research/faculty-staff/anne-churchland/#research-profile

https://www.ibiology.org/development-and-stem-cells/germ-cell Germ cells, which give rise to egg and sperm, are critical to the survival of a species. Lehmann describes how germ cells are specified in the early embryo and how they develop. Very early in embryogenesis, germ cells, the cells that give rise to egg and sperm, are set aside from the somatic cells which give rise to the rest of the cells in our bodies. While germ cells are not necessary for survival of the individual, they are crucial for survival of the species. In her first talk, Dr. Ruth Lehmann explains that there are two mechanisms by which germ cells are specified in the early embryo; via germ plasm or via induction. Germ cells specified via either mechanism have in common the presence of germ granules; large, membraneless, ribo-nuclear particles. Interestingly, certain families of RNA regulatory proteins are conserved in germ granules across species. Lehmann describes work from her lab and others on the life cycle of germ granules in Drosophila, including how they are assembled, their interesting biophysical properties and how proteins and RNAs are organized within the granules. In her second talk, Lehmann focuses on the establishment of the dichotomy between somatic and germ line fate. She explains how Drosophila germ cells develop to become so different from the somatic cells that make up the rest of the embryo. Germ cell development depends solely on maternal transcripts from the egg, while development of the soma depends on new zygotic transcription. Lehmann describes how two different molecular strategies, precise spatially controlled protein degradation and complete interference with the mRNA transcriptional elongation process, are employed to prevent somatic differentiation, thus allowing germ cell specific gene expression to occur. Speaker Biography: Ruth Lehmann is the Laura and Isaac Perlmutter Professor of Cell Biology, Chair of the Department of Cell Biology, and Director of the Skirball Institute of Biomolecular Medicine at the New York University School of Medicine. She is also an Investigator of the Howard Hughes Medical Institute. Lehmann received her PhD from the University of Tübingen with Christiane Nüsslein-Volhard where she identified and studied genes that establish polarity along the longitudinal axis of the fly embryo. Following a post-doc at the MRC Laboratory in Cambridge UK, Lehmann moved to the USA where she was a faculty member at MIT and the Whitehead Institute. In 1996, Lehmann joined the Skirball Institute where her lab is working to molecularly dissect germ cell development in Drosophila. Lehmann has been actively involved in the governance of several societies including the Society for Developmental Biology and the American Society for Cell Biology and she is on the editorial board of a number of journals. For her scientific and community contributions, she has been elected to the National Academy of Sciences (2005), American Academy of Arts and Science and the European Molecular Biology Organization (EMBO). In 2011, Lehmann was awarded the Conklin Medal of the Society for Developmental Biology and in 2018 the Keith Porter Award from the American Society for Cell Biology. Find out more about Lehmann’s research here: https://med.nyu.edu/faculty/ruth-lehmann and here: https://www.hhmi.org/scientists/ruth-lehmann

https://www.ibiology.org/development-and-stem-cells/germ-cell Germ cells, which give rise to egg and sperm, are critical to the survival of a species. Lehmann describes how germ cells are specified in the early embryo and how they develop. Very early in embryogenesis, germ cells, the cells that give rise to egg and sperm, are set aside from the somatic cells which give rise to the rest of the cells in our bodies. While germ cells are not necessary for survival of the individual, they are crucial for survival of the species. In her first talk, Dr. Ruth Lehmann explains that there are two mechanisms by which germ cells are specified in the early embryo; via germ plasm or via induction. Germ cells specified via either mechanism have in common the presence of germ granules; large, membraneless, ribo-nuclear particles. Interestingly, certain families of RNA regulatory proteins are conserved in germ granules across species. Lehmann describes work from her lab and others on the life cycle of germ granules in Drosophila, including how they are assembled, their interesting biophysical properties and how proteins and RNAs are organized within the granules. In her second talk, Lehmann focuses on the establishment of the dichotomy between somatic and germ line fate. She explains how Drosophila germ cells develop to become so different from the somatic cells that make up the rest of the embryo. Germ cell development depends solely on maternal transcripts from the egg, while development of the soma depends on new zygotic transcription. Lehmann describes how two different molecular strategies, precise spatially controlled protein degradation and complete interference with the mRNA transcriptional elongation process, are employed to prevent somatic differentiation, thus allowing germ cell specific gene expression to occur. Speaker Biography: Ruth Lehmann is the Laura and Isaac Perlmutter Professor of Cell Biology, Chair of the Department of Cell Biology, and Director of the Skirball Institute of Biomolecular Medicine at the New York University School of Medicine. She is also an Investigator of the Howard Hughes Medical Institute. Lehmann received her PhD from the University of Tübingen with Christiane Nüsslein-Volhard where she identified and studied genes that establish polarity along the longitudinal axis of the fly embryo. Following a post-doc at the MRC Laboratory in Cambridge UK, Lehmann moved to the USA where she was a faculty member at MIT and the Whitehead Institute. In 1996, Lehmann joined the Skirball Institute where her lab is working to molecularly dissect germ cell development in Drosophila. Lehmann has been actively involved in the governance of several societies including the Society for Developmental Biology and the American Society for Cell Biology and she is on the editorial board of a number of journals. For her scientific and community contributions, she has been elected to the National Academy of Sciences (2005), American Academy of Arts and Science and the European Molecular Biology Organization (EMBO). In 2011, Lehmann was awarded the Conklin Medal of the Society for Developmental Biology and in 2018 the Keith Porter Award from the American Society for Cell Biology. Find out more about Lehmann’s research here: https://med.nyu.edu/faculty/ruth-lehmann and here: https://www.hhmi.org/scientists/ruth-lehmann